We have shown recently that Mfn2 overexpression caused growth suppression in multiple cell lines by suppressing Ras-Raf-MEK-ERK signaling pathway. To investigate the physiological relevance of the anti-proliferative properties of Mfn2, we extended our studies to human peripheral blood T cells. We wanted to know what happens to the Mfn2 levels during T cell activation through T cell receptors. Our data have demonstrated that the activation-induced degradation of Mfn2 preceded the cells entry into the cell cycle. Pharmacological inhibitors (LY294002, a PI3 kinase inhibitor; rapamycin, an mTOR inhibitor; and A443654, an AKT inhibitor) that blocked the activation-induced degradation of Mfn2, also blocked the cell cycle. The blockage in Mfn2 degradation was not a general consequence of cell cycle inhibition, since late cell cycle blockers (aphidicolin, an S-phase blocker; and Nocodazole, a G2/M blocker) blocked the cell cycle without preventing the degradation of Mfn2. These data suggest that the activation-induced Mfn2 degradation is a pre-requisite for cells entry into the cell cycle. Over-expression of constitutively active AKT resulted in the downregulation of Mfn2, which can be blocked by a proteasome inhibitor. Akt-mediated downregulation of Mfn2 was via the mTORC1 pathway since (i) this downregulation was blocked by rapamycin, and (ii) over-expression of mTOR caused Mfn2 downregulation. Our data suggested that mTOR was involved in activation-induced ROS production, which in turn activated p38 MAP kinase resulting in the phosphorylation of Mfn2 and subsequent degradation. Collectively, our data suggest that PI3K-AKT-mTOR pathway plays an important role in activation-induced downregulation of Mfn2 and subsequent proliferation of resting T cells. It is known that T cells from aged mice have deficit in their proliferative capacities. To investigate the status of Mfn2 in the proliferative response of T cells from aged mice, naive and memory CD4+ T cells from young and old mice were activated through T cell receptor for 3 days, and the status of Mfn2 was determined by western blot analysis using whole cell lysates. The degree of activation-induced Mfn2 degradation was much less in memory as compared to nave populations, which correlated with the reduced proliferative capacities of memory as compared to naive populations. We are currently investigating the mechanisms responsible for the altered degradation of Mfn2 in memory populations irrespective of their age.